There are many factors that influence the addictiveness of a drug. The route of administration is a major determinant of the speed of drug entry into the body and to receptors in the central nervous system which produce resultant effects. Clinical studies are in progress which determine the importance of different routes of administration and the relationship of blood concentrations of drug and active metabolites to concomitant drug effects. Studies of heroin, cocaine, methamphetamine, codeine and marijuana administration by the intravenous, smoked, intranasal and oral routes are underway or have been performed. In order to study the pharmacokinetics of chronic cocaine use, multiple oral doses of cocaine are administered and concurrent physiological, behavioral and performance measures are collected along with blood specimens. Another new study examines oral administration of tetrahydrocannabinol, the primary psychoactive component of marijuana, in the form of Dronabinol (synthetic tetrahydrocannabinol) and hemp oil products. Pharmacodynamic effects include subjective, cognitive and psychomotor performance and physiological measures. Plasma, urine, saliva, sweat, hair, nails and skin are analyzed for drug and metabolites by solid phase extraction-gas chromatography/mass spectrometry. New analytical approaches, e.g., liquid chromatography/mass spectrometry, liquid chromatography/MS/MS, MALDI-TOF and chemical ionization gas chromatography/mass spectrometry, have been added to study the disposition of drug and metabolites in these alternative biological matrices. The intravenous and smoked routes produce a rapid onset of pharmacological effects together with an early appearance of drug and metabolites in blood. Evidence of delays in distribution to effector sites are observed following marijuana smoking, but drug effects following heroin and cocaine administration coincided more closely with concurrent blood concentrations. Onset of effects is delayed longer following intranasal administration and became pronounced after oral administration.